J-di-substituted pyrrolidine compounds



United States 1,3-DI-SUBST1TUTED PYRRGLIDINE COMPUUNDS Rolland Frederick Feidiramp and Yao Hua Wu, Evans ville, 1nd,, assignors to Mead Johnson & Company,

Evansville, Ind, a corporation of Indiana No Drawing. Application Gctoher 14, 1955 Serial No. 540,604 11 Claims. (Cl. 260-313} This invention relates to 1,3-di-substituted pyrrolidine compounds and has particular reference to compounds re lated to pyrrolidine containing the radical in which R represents an alkyl, allzenyl, aryl or aralkyl group.

This invention has more particular reference to those compounds having the formula CH2-CHGH2X used to prepare phenothiazine derivatives having a marked antihistaminic activity as well as some antispasmodic activity.

in accordance with this invention, the l-substituted-Elpyrrolidylmethyl alcohols having the formula OH2GHCH9OH E1 /CH2 may be prepared by reacting esters of itaconic acid with a suitable organic primary amine whereby to form a lsubstituted-3-carboall oxy-5-pyrrolidinone by ring closure. The substituent in the 1 position in the ring will be governed by the particular primary amine selected, representative primary amines being methylamine, ethylamine, n-propylamine, isopropylamine, allylamine, butylamine, aniline, benzylaminc or the like. The substituted pyrrolidinone is then completely reduced with a strong reducing agent, such as lithium aluminum hydride, in order to produce a carbiuol having the generic formula above indicated. These carbinols may be esterified by conventional methods with such organic acids as benzilic acid or the like to produce compounds having high antispasmodic activity, all as disclosed in our copending ap-. plication Serial No. 540,606, filed of even date herewith.

In order to produce the corresponding halides, the carbinols previously indicated may be reacted with a thionyl halide to form the l-substituted-3-pyrrolidylrnethyl halides. These methyl halides may be reacted with an amine, such as phenothiazine, to produce a compound having antispasmodic activity and an unexpectedly high antihistaminic activity, all as disclosed in our copending application Serial No. 540,605, filed of even date herewith.

2,826,588 Patented Mar. 11, 1958 For a more complete understanding of this invention, specific examples are here given which more fully disclose the compounds contemplated within the scope of this invention and their method of preparation.

l-ETHYL-3--CARBOMETHOXY-5-PYRROLIDINONE l-ETHYL-3 -PYRROLIDYLMETHY L ALCOHOL A solution of 171 parts of l-ethyl-3-carbomethoxy-5- pyrrolidinone in 108 parts of anhydrous ether was added slowly to a partial solution of 54 parts of powdered lithium aluminum hydride in 600 parts of ether. The addition was made over a period of 4-5 hours with eflicient stirring so as to maintain a moderate reflux rate. When the addition was complete, refluxing and stirring were continued for 2 hours, after which the reaction mixture was left overnight at room temperature. The white lithium aluminum complex was decomposed by the slow addition of 77 parts of water and sufficient additional ether to permit efficient stirring. The resulting thick slurry was stirred for an hour and then filtered by suction. This ether filtrate was set aside while the cake was completely extracted in a Soxhlet type apparatus with anhydrous ethanol. After combining the ether and alcoholic filtrates, the solvents were removed by distillation and the thick residual oil fractionated under reduced pressure. Yield of the substituted alcohol was 94.5 parts.

l-ETHYL-3-PYRROLIDYLMETHYL CHLORIDE A solution of 129.2 parts of 1-ethyl-3-pyrrolidylmethyl alcohol in 450 parts of chloroform was saturated with hydrochloric acid gas. The brown colored two phase mixture was then heated to refluxing and slowly treated with a solution of 240 parts of thionyl chloride in 450 parts of chloroform. When the addition was complete, refluxing was continued for an hour. After standing overnight, the excess thionyl chloride and solvent were partially removed by distillation and completely by two successive distillation washes with 200 parts of anhydrous ethanol. The residue was dissolved in 300 parts of water and all insoluble material completely removed from the solution by extraction with isopropyl ether. This acidic aqueous solution was made strongly basic with potassium hydroxide liberating the free basic chloride as an oil. The oil was extracted with ether and the extract dried with anhydrous magnesium sulfate. After filtration, all solvent was removed by distillation and the residual oil fractionated under reduced pressure. Yield of the chloride was 117 parts as a water clear oil.

In the foregoing examples the preparation of the lethyl compounds is specifically disclosed. The method outlined is equally applicable to the other l-substituted derivatives comprehended within the scope of this invention and a number of such compounds have been prepared utilizing the same methods and essentially the same molar ratio of reactants. Thus, as the following. tables will indicate, the corresponding methyLn-propyl, isopropyl, allyl, butyl, benzyl and phenyl derivatives have been prepared.

In Table l are presented the physical properties and analyses of a number of 1-substituted-3-carboalkoxy-S- pyrrolidinones prepared in accordance with the procedure indicated above.

Table I'.-1 -substituted-3-carb0alk0xy-5-pyrr0lidinmz es GHQ-" H- C O O R As previously indicated, the substituted group in the 1 position may be alkyl, allrenyl, aryl or aralltyl and will O= CH4 ring closure with an ester of itaconic acid. in the foregoing description the dimethyl ester of itaconic acid has it been particularly specified as one of the starting compounds but it will be readily aparent to one skilled in the Carbon H dro on R R B. P., P, 1!. y g

C. mm.

Calcd Found Calcd. Found CH3- 0:115 166-167 19 0 1. 4678 56.18 56. 68 7. 65 7. 82 0;!1 CH3 104-106 0 18 1.4702 56.13 56.21 7.65 7.35 CiH7 CH3 91. 5-92 0 08 1.4688 58.36 57. 82 8.16 7.82 1-0311'1- CH1 86-88 0 06 1.4665 58.36 58. 60 8.16 8.12 0H=0H-GE 0H3 178-179 21 0 1.4829 59. 00. 59.40 7.15 6.84 4 CH 180-182 18 0 1.4682 60.28 60.80 8.60 8. 63 CsH5OHg CH3 1 64-65 66- 93 67. 6. 48 6. 38 5115 CH; 1 71-73 65. 74 65.80 5. 98 5.87

1 Melting point, C.

In Table II are presented the physical properties and analyses of a number of 1-substituted-3-pyrrolidylmethyl alcohols prepared in accordance with the procedure given above for the preparation of the ethyl derivative.

Table Il.-1-substituted-3-pyrrolidylmethyl alcohols CHz-OHCHa-OH art that other esters may be employed, such as the diethyl, di-n-propyl, di-isopropyl, dibutyl and the like.

In connection with the preparation of the lsubstituted- S-pyrrolidylmethyl chloride as above indicated, it will be readily appreciated that other halides be obtained by methods similar to that indicated above except that the appropirate thionyl halide is employed in place of the specifically designted thionyl chloride. Thus the corre- -CH2 CH1 1 sponding thionyl bromides or lodldes my be similarly used to prepare the corresponding substituted 3-pyrroll I 1 R ldyhnethyl bromides or iodides.

Carbon Hydrogen R B. P., P, 71

C. mm

Calcd. Found Calcd. Found CHF- 94-96. 5 15. 0 1. 4662 62. 59 62. 27 11. 37 11. 19 0411? 110-111 20. 0 1. 4698 65. 07 65. 84 11.70 11.86 CaH7- 122-126 24. 0 1. 4669 67. 08 67. 05 11. 97 11. 75 1C3H1 122-122. 5 24. 0 1. 4718 67. 08 67. 15 11. 97 11. 61 CHF=GI CHz- 122-124 21. 0 1. 4822 08. 04 68. 22 10. 71 11.01 04m 130-131 19. 0 1. 4672 68. 74 69. 89 12. 9 12. 14 cum-0H4- 166-168 12. 0 1. 5481 75. 85 75. 29 8. 96 8. 89 QQHIS 131 25 0. 05 1. 5872 74. 54 74. 56 8. 53 8. 39

1 Melting point, C.

In Table III there are presented the physical constants and the analyses of the various 1-substituted-3-pyrrolidylmethyl chlorides that have been prepared in accordance with the'procedure given above in connection with the preparation of the l-ethyl derivative.

Table III.1-substituted-3-pyrrolidylmethyl chlorides It will be appreciated from the foregoing considerations that a new class of chemical compounds has been produced in accordance with this invention and, as will be apparent from our copending applications Serial Nos. 540,605 and 540,606, these compounds have particular utility as intermediates in the synthesis of other compounds having pronounced physiological activity. Reference has been made to a number of specific compounds per se but it will be readily apparent that the simple acid addition or quaternary ammonium salts of these compounds also fall within the scope of this invention. Suitable acid addition salts are those of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, hydro-indie acid, sulfuric acid, phosphoric acid, malcic acid, acetic acid, citric acid, succinic acid, tartaric acid and the like. Suitable quaternary ammonium salts of these compounds are those formed by the addition to the basic compou 1113 of such compounds as methyl chloride, bromide or iodide. ethyl bromide, propyl chloride, benzyl chloride, benzyl bromide, methyl sulfate, methyl benzenesulfonate, methylp-toluene sulfonate or other alkyl or aralkyl esters of inorganic acids or organic sulfonic acids.

While particular embodiments of this invention are shown above, it will be understood, of course, that the invention is not to be limited thereto, since many modifications may be made, and it is contemplated, therefore, by the appended claims, to cover any such modifications as fall within the true spirit and scope of this invention.

We claim:

1. A I i-substituted pyrrolidine compound having the formula wherein X is selected from the group consisting of hydroxyl and a halogen and wherein R is selected from the group consisting of lower alkyl, lower alkenyl, monocyclic aryl and phenyl lower alkyl.

2. The compound recited in claim 1 methyl.

3. The ethyl.

4. The compound recited in claim 1 isopropyl.

5. The compound recited in claim 1 benzyl.

6. The compound recited in claim 1 wherein R is allyl.

7. l-lower alkyl-3-pyrrolidylmethyl alcohol.

8. l-lower alkyl-3-pyrrolidylmethyl chloride.

wherein R is compound recited in claim 1 wherein R is wherein R is wherein R is 6 9. l-monocyclic aryl-3-pyrrolidyhnethyl alcohol.

10. l-monocyclic aryl-3-pyrrolidylmethyl chloride. 11. A process of preparing a compound having the formula CH2-CH-CH2OH References Cited in the file of this patent UNITED STATES PATENTS Blicke May 10, 1955 OTHER REFERENCES Beilstein: Hand. Org. Chem., 4th ed., Band XXI, 1st Suppl., pp. 189-190.

I. A. C. 8., vol. 60, pp. 402-6 (1938)..

J. A. C. 8., vol. 73, pp. 2402*2403 (1.951).

Chem. Abs., vol. 45, p. 10237f (1951). 

1. A 3-SUBSTITUTED PYRROLIDINE COMPOUND HAVING THE FORMULA 